The subject matter of the invention is 2-arylquinoline derivatives, their preparation and their application in therapeutics.
The compounds correspond to the general formula (I) 
in which:
A represents a hydrogen atom, a hydroxyl, a C1-3 alkoxy group, a hydroxy(C1-6 alkyl) group, a (C1-3 alkoxy)(C1-3 alkyl) group, a thiol, (C1-6 alkyl)sulfanyl or a halogen;
B and D represent, independently of one another, a hydrogen atom, a C1-6 alkyl group, a fluoro(C1-6 alkyl) group or a perfluoro(C1-2 alkyl) group or B and D together from an oxo;
R1 represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and, as heteroatom, an oxygen, a sulfur or a nitrogen; it being possible for the phenyl, the naphthyl or the heteroaryl to be substituted by one, two or three substituents chosen from the group consisting of a halogen, a hydroxyl, a nitro, an amino, an azido, a C1-6 alkyl group, a hydroxy(C1-6 alkyl) group, a (C1-6 alkyl)carbonyl group, a (C1-6 alkyl)amino group, a di(C1-6 alkyl)amino group, a fluoro(C1-6 alkyl) group, a perfluoro(C1-2 alkyl) group, a C1-6 alkoxy group, a phenyl and a benzyl, and a benzyloxy;
R2 and R3 represent, independently of one another, a hydrogen atom, a halogen or a C1-6 alkyl group,
R4 represents a hydrogen atom, a hydroxyl or a halogen, and
R5 and R6 represent, independently of one another, a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a fluoro(C1-6 alkyl) group or a perfluoro(C1-2 alkyl) group or R5 and R6 together form a C2-6 alkylene chain or a C3-6 alkenylene chain, to give, with the nitrogen to which they are attached, a heterocycle, such as, for example, a piperidyl, azetidinyl or pyrrolidyl, this heterocycle optionally being substituted by a C1-4 alkyl group; and their salts.
The preferred compounds according to the invention are chosen from the following subgroups, in which:
A represents a hydrogen, hydroxyl, a thiol or a halogen and more particularly a hydroxyl; and/or
B and D represent a hydrogen atom; and/or
R1 represents a phenyl, a naphthyl or a heteroaryl comprising 4 or 5 carbon atoms and, as heteroatom, a sulfur or a nitrogen, it being possible for the phenyl, the naphthyl or the heteroaryl to be substituted by one, two or three substituents chosen from the group consisting of a halogen, a hydroxyl, a nitro, an amino, an azido, a C1-3 alkyl group, a hydroxy(C1-3 alkyl) group, a (C1-3 alkyl)carbonyl group, a (C1-3 alkyl)amino group, a di(C1-3 alkyl)amino group, a fluoro(C1-6 alkyl) group, a perfluoro(C1-2 alkyl) group, a C1-3 alkoxy group, a phenyl, a benzyl and a benzyloxy; and/or
R2 and R3 represent, independently of one another, a hydrogen atom or a C1-6 alkyl group, more particularly a C1-3 alkyl group; and/or
R5 and R6 represent, independently of one another, a hydrogen atom or a C1-6 alkyl group, more particularly a C1-3 alkyl group, or R5 and R6 together form a C2-6 alkylene chain, to give, with the nitrogen to which they are attached, a heterocycle, such as, for example, a piperidyl, azetidinyl or pyrrolidyl, more particularly piperidyl, this heterocycle optionally being substituted by a C1-4 alkyl group, more particularly a C1-2 alkyl group.
A particularly preferred subgroup of compounds of formula (I) is that in which A, B, D, R1, R2, R3, R5 and R6 are as defined above in the subgroups of preferred compounds and R4 is as defined above.
In particular, the following subgroup of compounds is particularly preferred:
A represents a hydroxyl,
B and D and R4 represent a hydrogen atom,
R1 represents a naphthyl, a thiophene, a pyridine or a phenyl, it being possible for the phenyl to be substituted by one, two or three substituents chosen from the group consisting of a a halogen, a hydroxyl, a nitro, an amino, an azido, a C1-3 alkyl group, a hydroxy(C1-3 alkyl) group, a (C1-3 alkyl)carbonyl group, a (C1-3 dialkyl)amino group, a perfluoro(C1-2 alkyl) group, a C1-3 alkoxy group, a phenyl and a benzyloxy,
R2 and R3 represent, independently of one another, a hydrogen atom or a C1-3 alkyl group, and
R5 and R6 represent, independently of one another, a C1-3 alkyl group or R5 and R6, together with the nitrogen to which they are attached, a piperidyl, this piperidyl optionally being substituted a C1-2 alkyl group.
The preferred compounds are shown in the table below; mention may more particularly be made of the following compounds:
2-Phenyl-3-methyl-8-(1-diethylamino-2-hydroxyethyl)quinoline,
2-Phenyl-3-methyl-8-(1-(R)-[2xe2x80x2-(R)methylpiperidino]-2-hydroxyethyl)quinoline,
2-Phenyl-8-(1-diethylamino-2-hydroxyethyl)quinoline,
2-Thiophen-2-yl-8-(1-diethylamino-2-hydroxyethyl)quinoline, and
2-(2-Fluorophenyl)-3-methyl-8-(1-diethylamino-2-hydroxyethyl)quinoline.
In the present application:
C1xe2x88x92z (or C2xe2x88x92z or C3xe2x88x92z), where z can take the values between 2 and 6, represents a carbonaceous chain which can have from 1 (or 2 or 3) to z carbon atoms,
the term alkyl, alkenyl or alkoxy respectively represents an alkyl, alkenyl or alkoxy with a linear or branched carbonaceous chain,
the term alkylene or alkenylene respectively represents a divalent alkyl or alkenyl with a linear or branched carbonaceous chain,
the term heteroaryl represents an aromatic ring comprising 4 or 5 carbon atoms and a heteroatom; such a ring is, for example, a thiophene, a furan or a pyridine,
Pg represents a protective group; examples of protective groups and protection and deprotection methods are given in Protective Groups in Organic Synthesis, Greene et al., 2nd Ed. (John Wiley and Sons Inc., New York), and
halogen represents an iodine, bromine, chlorine or fluorine atom.
The compounds of general formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and their mixtures, including racemic mixtures, form part of the invention.
When a compound according to the invention exhibits stereoisomerism, for example of axial-equatorial or Z-E type, the invention comprises all the stereoisomers of these compounds.
The compounds of general formula (I) can be provided in the form of the free base or in the form of addition salts with acids, which also form part of the invention. These salts, according to the present invention, comprise those with inorganic or organic acids which make possible suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphorsulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, maleate, pamoate, fumarate, 2-naphthalenesulfonate or para-toluenesulfonate. Even if the pharmaceutically acceptable salts are preferred, the other salts form part of the present invention. These salts can be prepared according to methods known to a person skilled in the art, for example by reaction of the base with the acid in an appropriate solvent, such as an alcoholic solution or an organic solvent, and then separation from the medium in which they are present by evaporation of the solvent or by filtration.
The compounds of the invention can be prepared by processes illustrated by the schemes which follow.
The compounds of formula (I), in particular those for which A represents hydroxyl, can be prepared according to the process described in scheme 1. 
According to this process, a quinoline derivative of formula V, in which Y represents a nucleofuge group, such as a halogen or an activated hydroxyl group, for example activated in the triflate form, is reacted by palladium-catalyzed Stille coupling with a compound of formula VI, under the conditions defined by McKean, D. R.; Parinello, G.; Renaldo, A. F.; Stille, J. K., J. Org. Chem., 52, 1987, 492, to give an ethenyl derivative of formula IV.
The ethenyl derivative of formula IV thus obtained is reacted with an oxidizing agent, such as sodium periodate, osmium tetroxide or meta-chloroperbenzoic acid, followed by hydrolysis in a basic or acidic medium, according to conventional methods known to a person skilled in the art, to form a diol of formula III. It is also possible to use AD-mix to obtain asymmetric hydroxylation in an alcoholic solvent, such as, for example, a mixture of tert-butanol in the presence of water, at a temperature preferably of between xe2x88x9210xc2x0 C. and 5xc2x0 C.
The hydroxyl group geminal to the B group of the compound of formula III is selectively protected by a protective group Pg according to methods known to a person skilled in the art, for example by formation of a silyl ether, such as, for example, the tert-butydinethylsilyl ether, so as to obtain the compound of formula II in which Pg represents a protective group. The hydroxyl group carried by the carbon alpha to the quinoline of the compound of formula II thus obtained can subsequently be optionally activated, in a way known to a person skilled in the art, so as to obtain a nucleofuge group, such as a mesyl group, a tosyl or a bromine atom.
The compound of formula (I) according to the invention is subsequently prepared from the latter compound by reacting it with an amine NHR5R6. This reaction can be carried out in an aprotic organic solvent, such as chloroform or methylene chloride, at a temperature between ambient temperature and the reflux temperature of the solvent, in the presence of an excess of amine (from 0.2 to 100 equivalents in excess).
The compound is subsequently deprotected according to methods known to a person skilled in the art to give the compound of formula (I). The meanings of R1, R2, R3, R4, R5, R6 and B in each of the compounds of formulae II, III, IV, V and VI and of the amine NHR5R6 are those indicted for the formula (I).
The compound of formula V and also the compound of formula IV can be prepared according to methods disclosed in PCT/FR99/02129 and French application No. 9814389.
Alternatively, it is possible to prepare the compounds of formula V according to the methods described below.
Thus, the compounds of formula V can be prepared either by a Skraup or Doebner-Miller reaction, according to reaction scheme 2. 
According to this process and under the conditions defined by Belser P. (Tetrahedron, 1996, vol. 52, No. 8, 2937-2944) or advantageously under the conditions defined by Z. Song J. (Heterocyclic Chem., 1993, 30, 17-21), an aniline of formula VII, for which Z represents a hydroxyl or methoxy group, and an xcex1,xcex2-unsaturated aldehyde or an xcex1,xcex2-unsaturated ketone formula VIII are heated in the presence of a dehydrating agent, such as sulfuric acid, and of an oxidizing agent, such as sodium iodide, to form a quinoline derivative, substituted in the 8 position by Z, of formula IX. This compound is then treated with an aryllithium (or heteroaryllithium) derivative, denoted by R1xe2x80x94Li, in a solvent, such as toluene, to give a compound of formula V.
The meanings of R1, R2, R3 and R4 of the compounds of formula V, VII, VIII and IX are those indicated in the formula I.
The compounds of formula V can also be prepared by a Friedlxc3xa4nder condensation reaction reaction scheme 3. 
According to this process and under the conditions defined by R. P. Thummel et al. (J. Org. Chem., 1993, 58, 1666-1671), an aryl (or heteroaryl) ketone of formula XI is reacted with a 2-acylaniline of formula X, in which W represents a halogen, such as iodine, bromine or chlorine, or a hydroxyl or methoxy group, in a solvent with a high boiling point, such as toluene, in the presence of alcoholic potassium hydroxide. In the case where W is a hydroxyl or methoxy, this reaction is followed by the conversion of these groups into the leaving group Y as defined above, according to methods known to a person skilled in the art, to give the compounds of formula V. For example, in the case where W is a methoxy, the latter is converted first into a hydroxyl, by the action of boron tribromide in a solvent, such as dichloromethane or chloroform, at a temperature preferably of xe2x88x9230xc2x0 C. to 0xc2x0 C. The hydroxyl is subsequently converted into a leaving group, for example by the action of trifluoromethanesulfonic anhydride in a solvent, such as pyridine, at temperatures preferably of between xe2x88x9210xc2x0 C. and 5xc2x0 C.
The meanings of R1, R2, R3 and R4 of the compounds of formula V, X and XI are those indicated in the formula (I).
Moreover, the compounds of formula (I), in particular those for which A represents a hydroxyl group, can also be prepared, according to scheme 4, from a quinoline derivative of formula XII, for which Y is as defined above, by a palladium-catalyzed Stille or Suzuki coupling (Chem. Rev., 1995, 95, 2457-2483) with a compound of formula XIII or XIV. The meanings of R1, R2, R3, R4, R5 and R6 of the compounds of formula XII, XIII or XIV are those indicated for the formula I. 
The compound of formula XII can be prepared according to the process described in scheme 5.
According to this process, a quinoline compound of formula XX is oxidized, by methods known to a person skilled in the art, to an N-oxide compound of formula XIX, which, in the presence of acetic anhydride and under the conditions defined in the patent of Tzeng, C. et al., U.S. Pat. No. 5,646,164, rearranges into a 2-acetoxyquinoline compound of formula XVIII. The hydroxyl group in the 8 position of the latter is converted to a nucleofuge group, such as a triflate group, according to methods known to a person skilled in the art, and then is brought together with a compound of formula VI by palladium-catalyzed Stille coupling, under the conditions defined by McKean, D. R. et al. (J. Org. Chem., 52, 1987, 492), to provide the ethenyl derivative of formula XVII. The acetoxy group in the 2 position of the latter derivative is subsequently converted into a Y group, representing a nucleofuge group, such as a halogen or an activated hydroxyl group, for example into a triflate, to give the ethenyl derivative of formula XVI. The quinoline derivative of formula XII can subsequently be prepared according to the reaction sequence described in scheme 1, from the quinoline of formula XVI thus obtained. The meanings of R2, R3, R4 and B of the compounds of formula XVI, XVII, XVIII, XIX and XX are those indicated in the formula I. 
The compounds of formula (I) according to the invention in which A is not a hydroxyl group can be prepared from the compound of formula (I) where A is a hydroxyl group according to scheme 6.
According to this scheme, these compounds can be prepared from the compound of formula (I) where A is a hydroxyl group by activation of this group in a way known to a person skilled in the art, so as to obtain a nucleofuge group Y as defined above, and by then reacting the latter with a nucleophilic group XV xe2x80x9cAxe2x80x9d. This nucleophilic group corresponding to the corresponding nucleophilic entity of the substituent A. The reaction can be carried out, for example, in a solvent, such as tetrahydrofuran, and by heating to the reflux temperature of the solvent. 
Also according to this scheme, the compounds of formula (I) according to the invention for which A is a hydrogen atom can be prepared by dehydroxylation of a corresponding compound of formula (I) where A is a hydroxyl group. The dehydroxylation reaction can be carried out in a way known to a person skilled in the art, for example by reaction with triethylsilane in trifluoroacetic acid while heating to the reflux temperature.
The compounds of formula (I) according to the invention for which A and D are hydrogen atoms can also be prepared according to the following reaction scheme 7. 
According to this process, the compound of formula (I) is prepared by reacting a nucleophilic derivative of formula Bxe2x80x94CH2MX, for which M represents a metal, X represents a halogen and B has the meaning indicated for the formula (I), such as, for example, an organomagnesium compound or an organolithium compound, with an amine derivative of formula XXIII obtained by reaction of a secondary amine of formula NHR5R6, for which the meanings of R5 and R6 are those indicated for the formula (I) with the exception of the hydrogen atom, with an aldehyde of formula XXII. The reaction can be carried out in an organic solvent, such as toluene or benzene, at reflux, with azeotropic distillation. The meanings of R1, R2, R3, R4, R5, R6 and B of the compounds XXII and XIII are those indicated for the formula (I).
The starting materials (VI, VII, VIII, X, XI, XIII, XIV, XX, XXII, HNR5R6, Bxe2x80x94CH2MX) for the syntheses of the compounds of formula (I) are directly available commercially, are known in the literature or can be synthesized by conventional methods known to a person skilled in the art.
The following examples illustrate the processes and techniques appropriate for the preparation of this invention, without, however, limiting the scope of the claim. The microanalyses and the NMR and IR spectra confirm